2-chloro-11beta, 21-dihydroxy-4, 17(20)-[cis]-pregnadiene-3-one and 21-acyl esters thereof



2,865,936 2-CHLOR0-1l;3,21-DIHYDROXY 4,17(2)-[CIS]- PREGNADIENE-3-ONE AND ZI-ACYI. ES- TERS THEREQF 5 William P. Schneider, Alan H. Nathan, and .Iohn A. Hogg, Idalamazoo Township, Kalamazoo County, Mich, as

signers to The Upjohn Company, Kalamazoo, Mich, a corporation of Michigan No Drawing. Original application May 23, 1955, Serial No. 519,517. ivided and this application January '7, 1957, Serial No. 632,633

5 Claims. (Cl. 260.37.45)

This invention relates to novel 2-halogenated steroids and especiallyLchloro-llfi,17o,21-trihydroxy-,4-pregnene- 3,20-dione and ZI-esters thereof, to novel steroid intermediates in the production of these compounds and to a process for their production.

This invention is a division of application S. N. 510,517, filed May 23, 1955.

The novel compounds of the present invention and the process for their production may be represented by the following formulae:

. cortisone and its 21-esters and treatment of inflammatory ailments and are employable or hotel group according to methods known in the art,

e. g., reaction of I with ethylene trimethylene alcohol, etc., H1 the presence of an. acidiccatalyst, is productive of II. Reduction of II with lithium aluminum hydride, sodium aluminum hydride .orequivalent chemical reducing agent capable of reducing a 'carboxylic group to ca hinol is productive of a 3ketone-protec ted 2- chloro llfi,2l dihydroxy 4,17(20)'- '[cis] pregnadiene-3-one (III). Hydrolysis of the 3- ketoneprotecting group with aqueous acid is productive of 2-chloro-l 15,21- dlhydroxy-4, 1 7 (20) [cis] -pregnadiene-3-one (IV) Acetylation of the ZI-hydroxy 3-ketone protecting group is productive of a 3-ketoneprotected 2 chloro hydroxy-2l-acyloxy-4,17(20)- [cis]-pregnadiene-3-one (III, R' is Ac), which can be selectively hydrolyzed to V 21-acyloxy-4,l7(20)-[cis]-pregnadiene-3one (V). Oxidative hydroxylation of IV or a ZI-ester thereof (V) with, for example, osmium tetroxideand:hydrogen peroxide, is productive of Z-ChlOIO-llfi,l7zx,2l-ilihYdIOXY-4 pregnene-3,20-dione (VI, R' is H) and 2l-esters thereof (VI, R is Ac), respectively.

A 2 chloro 3-keto -11 oxygenated -.4,17(20) [cis]-pregnadiene-2l-carbonyloxy steroid (I) .isprepared as described in the copending application of Hogg, Beal,

glycol, propylene glycol,

methanol to produce methyl 2-chloro- 3,1l-diketo-4,17(20)*[cisJ-pregnadiene-Zl-oate (I, R is Substituting llp-hydroxy-progesthe starting steroid productive of the and ethanol, is productive of other loWer-alkyl esters of 2-chloro-3,1l-diketo-4,17(20)-[cis]- pregnadiene-Zl-oic acid and 2-chloro-3-keto-1lfi-hydroxy- 4,17(20)-[cisl-pregnadiene-Zl-oic acidr The Z-chloro compounds (I to VI) canbe reacted with a metal fluoride under exchange reaction conditions to produce the corresponding fluoro compounds.

and ZI-esters thereof in the spending 2-chloro compounds. Reacting 2-chloro-1'1fl,21- dihyd1oXy-4,17( 20)-pregnadiene-3-one (IV) or v 2l-ester thereof (V) with sodium iodide inacetone is productive of the corresponding 2-iodo compound which is converted to Z-iodohydrocortisone and 2l-esters thereof in the same manner as the corresponding 2 -chloro compounds. The Z-bromo compounds (IV to VI)" are similar ly prepared by substituting bromine for chlorine in the preparation of compound I which produce 2-bromohydrocortisone and 2l-esters thereof. I V V Oxidation of the 2-chloro-, 2-fluoro-, Z-bromoor 2- iodo-compound V1, with N-bromoacetamide in tertiary 'butyl alcohol is productive of the corresponding 11am compounds, i. e., 2-halo-cortisone and Zl-esterspthereof which also possess adrenal cortical hormone activity.

The Z-haIogenated cortical hormones, i. e., 2-halohydrocortisone, 2-ha1ocortisone, and 2l-e sters thereof, have adrenal cortical hormone activity. The 2-chlorohydro' cortisone and its 21-esters (VI), e. g., the acetate, have the adrenal cortical activity of the corresponding hydroare eflicacious in the messes glycol, methyl alcohol, ethyl alcohol, benzyl" produce 2 -chloro- 1 l s-hydroxy- --inventirwrfticularly the as an imp'roved alternative for the natural hormone in I the treatment of maladies in both humans and valuable domestic animals, e. g., in inflammations of the skin and eyes caused by bacterial or fungal infections, contact (dermatitis or other physiological maladjustment.

The 2-halogenated cortical hormones of the present Z-chlorohydrocortisone and 21- esters thereo, 'are -especiallyiseful in'pharmaceutical compositions and mixtures, e. gI,"ointments, lotions, greases, creams, aqueous suspensions, etc., for topical use. Incorporation of an antibiotic, especially neomycin sulfate, in an ointment, has surprising therapeutic advantages with each active ingredient potentiating and supplementing the useful properties of the other.

The following preparations and examples are illustrative ofthe products of the present invention and a process fortheir production, but are not to be construed as limitmg.

PREPARATION 1 Methyl 2-chlor'o-3 ,1 1 -diket-4 ,1 7 [cis] -pregnadiene- 21-0ate A solution of 6.57 grams (0.02 mole) of ll-ketoprogesterone in 100 milliliters of tertiary butyl alcohol was prepared at seventy degrees centigrade in an atmosphere of nitrogen. When the temperature of the solution dropped to-55 degrees Centigrade, there was added with stirring 11.7 grams (0.08 mole) of ethyl oxalate and 2.70 grams of sodium methoxide (0.05 mole) as a 25 percent solution in methanol, all in an atmosphere of nitrogen. Stirring was continued for about fifteen minutes while permitting the temperature to drop to about 37 degrees centigrade. A solution of 1.70 grams of glacial acetate acid and 2.46 grams of sodium acetate in 160 milliliters of methanol, cooled to ten degrees centigrade, was then added. The resulting dark green solution was cooled to about zero degrees centigrade and chlorine gas was added until the solution turned cloudy and white and a positive test for halogen on moistened starchpotassium iodide paper was obtained. The mixture was stirred for five minutes and, if a negative test for halogen was obtained, more chlorine was added until a positive test was obtained. This procedure was repeated until a persistent positive test was important, however, not to add more than just enough chlorine to give a positive test. The temperature of the reaction mixture was maintained at between zero and five degrees centigrade during the chlorination which took about forty'minutes.

To the resulting halogenated mixture was added 4.536 grams of sodium methoxide as a 25 percent solution in methanol. The temperature of the reaction mixture was permitted to rise to about 25 degrees centigrade. The mixture was maintained at this temperature for two hours and then poured into 1.7 liters of a mixture of ice and water. The resulting steroidal precipitate was filtered, washed thoroughly with water, filtered and dried. The dried crude product weighed 7.67 grams and melted at 100 to 120 degrees centigrade.

. The precipitate was dissolved in benzene and poured.

. over a column of thirty grams of Florisil synthetic magnesium silicate. The column was washed with a total volume of 390 milliliters of benzene and then developed. with 130 milliliters of Skellysolve B hexane hydrocarbons plus ten percent acetone. The eluate fractions contain ing the bulk of the crystalline material were combined to give 3.51 grams of methyl 2-chloro-3 ,11-diketo-4,17 (20)- pregnadiene-Zl-oate melting at about 185 to 189 degrees. centigrade. Recrystallization of these crystals from ethyl acetate gave colorless prisms melting at 192 to 193' degrees centigrade, having an [@1 of plus 214 degrees in chloroform and the analysis below.

Calculated for C I-1 C10 C, 67.58; H, 6.96; Cl, 9.07,. Found: C, 67.94; H, 6.84; Cl, 8.46.

for halogen was obtained. It L PREPARATION 2 T he 3-ethylene glycol ketal of methyl 2-chl0ro 3,11-di- Item-4,1 7 (20 -[cis] -pregnadiene-21-0are A solution of 3.71 grams of methyl 2-chloro-3,11 diketo-4,17(20) [cis] pregnadiene 21 oate and 0.360 gram of paratoluenesulfonic acid dissolved in a mixture of 180 milliliters of benzene and ten milliliters of ethylene glycol was refluxed for eight hours with continual removal of the water of reaction by a water trap. The cooled benzene solution was shaken with aqueous sodium bicarbonate, dried and then poured over a chromatographic column of 220 grams of Florisil magnesium sili cate. The column was developed with nine 300-milliliter portions of Skellysolve B plus four percent acetone and six 300-milliliter portions of Skellysolve B plus eight percent acetone. The sixth through twelfth 300-rnilliliter eluate fractions contained 3.37 grams of the S-ethylene glycol ketal of methyl 2-chloro-3,11-diketo-4,17(20) [cisl-pregnadiene-Zl-oate whose melting point varied from about 147 to about 203 degrees centigrade with no apparent difference in purity. The infrared absorption spectrum of this product was consistent with the structure. The product had an E of 11,225 and the analysis below.

Calculated for C H ClO C, 66.27; H, 7.18; Cl, 8.15. Found: C, 66.38; H, 7.35; Cl, 7.63.

PREPARATION 3 The 3-benzyl enol ether of methyl 2-chl0r0-3,l1-diketo- 4,l7(20)-[cisl-pregnadiene-21-oate EXAMPLE 1 The 3-ethylene glycol ketal of 2-chlm'0-11{3,21-dihydroxy- 4,17(20)-[cisl-pregnadiene-3-0ne To a solution of 0.5 grams of lithium aluminum hydride in milliliters of ether was added a solution of 1.71 grams of the 3-ethylene glycol ketal of methyl 2-chloro-3,l l-diketo 4,17 (20) [cis] pregnadiene 2loate in thirty milliliters of benzene. The mixture was stirred for one hour and then decomposed by the addition of 2.4 milliliters of ethyl acetate followed by one milliliter of water. The ether layer was decanted and the residual salts Washed thoroughly with ether. The combined ether solutions were evaporated to dryness to give 1.477 grams of the 3-ethylene glycol ketal of 2 chloro ll 8,2l-dihydroxy-4,l7(20)-[cis]-pregnadiene- 3-one melting at 156 degrees centigrade with decomposition. Recrystallization of these crystals from ethyl acetate gave product melting at 156.5 to 157.5 degrees centigrade with decomposition and having the analysis below.

Calculated for C H ClO Cl, 8.67. Found: Cl, 8.14, 8.81.

EXAMPLE 2.

The S-benzyl enol ether of Z-chloro-IIBQI-a'ihydroxy- 4,] 7(20)- [cis] -pregnadiene-3-0ne Following the procedure described in Example 1, but substituting the 3-benzyl enol ether of methyl 2-chloro- 3,1l-diketo-4,l7(20)-[cis]-pregnadiene 21 oate as the starting steroid, there is thus produced the 3-benzyl enol ether of 1118,21-dihydroxy-4,17(20)-lcis]-pregnadiene-3 one.

EXAMPLE 3 assertsv 5 perature for four hours. The solution was poured into water to. give a white'gumwhich"crystallized' uporrtritu ration with a ten percent aqueous solution ofhydro- The crystals, upon drying, weighed 255 3-ethylene glycol ketal of 2-chloro 11;? hydroxy 2'1- acetoxy 4,l7(20)-[cis]-pregnadiene 3 one melting at 143 to 144 degrees Centigrade and having the analysis below.

Calculated for C H ClO Cl, 7.86; acetyl, 9.54. Found: Cl, 7.90; acetyl, 9.1. 1

EXAMPLE 4 The 3-benzyl enol ether of 2-chl0r0-IIB-hydr0xy-2Z-acetxy-4,17(20- [cis] -pregnadiene-3-0ne Following the procedure of Example 3, but substituting the 3-benzyl enol ether of 2-chloro 115,21- dihydroxy- 4,17(20)-[cis]-pregnadiene-3-one as the starting steroid, there is thus produced the 3-benzyl enol ether of 2-chlorollfi-hydroxy 21 acetoxy-4,17(20) [cis]-pregnadiene- 3-one.

EXAMPLE 5 2-chl0r0-I IB-hydroxy-ZI -acel0xy-4,I7 cis] -pregnadiene-3-0ne 169.5 to 171 degrees Centigrade, having an E of 17,200, and the analysis below.

Calculated for C H ClO C, 67.88; H, 7.68; CI, 8.71. Found: C, 66.42; H, 7.56; Cl, 7.56.

EXAMPLE 6 2-chlore-11,821-dihydroxy-4,I 7 (20) [cis] -pregnadiene- 3-0ne Following the procedure described in Example 5, 2- chloro-l1,8,21-dihydroxy-4,l7(20)-[cis]-pregnadiene 3- one is produced by the hydrolysis of the 3-ethylene glycol ketal of 2-chloro-l1 6,2l-dihydroxy-4,17(2O)-[cis]-preg nadiene-B-one or the 3-benzyl enol ether of 2-ch1oro-1lfi, 2 1-dihydroxy-4, 1 7 20) cis] -pregnadiene-3-one.

EXAMPLE 7 2-chl0r0-JJB-hydr0xy-2I-acet0xy-4,17(20) [cis] -pregnadiene-3-0ne A solution of 122 milligrams of 2-chloro-llfi,2l-dihy- -droxy-4,l7(20)-[cis]-pregnadiene-3-one was dissolved in a mixture of 1.5 milliliters of acetic anhydride and 2.25 milliliters of dry pyridine. The mixture was maintained at about degrees Centigrade for about sixteen hours. The excess acetic anhydride was then decomposed with ice water and the resulting gummy precipitate was extracted with benzene. The benzene solution was washed with cold dilute hydrochloric acid, cold aqueous sodium bicarbonate and finally with Water and then dried. The dried benzene solution was distilled to dryness. The residue consisted of essentially pure, crystalline 2-chloro- 1lfi-hydroxy-Zl-acetoxy-4,17(20)-[cis]-pregnadiene 3- one. Recrystallization of this product from a mixture of ethyl acetate and Skellysolve B gave 2-chloro-11/3-hydroxy-2 l-acetoxy-4,17(20')-[cisl-pregnadiene ii-onemeltingat 1'69 to-171 degrees centigrade.

Similarly; 2-chloro-11 3,21-dihydroxy-4,17(2 0)'-. [cisJ- pregnadiene-3-one is converted to other 2-chloro-1lfl-hydroxy-21-acyloxy-4,17(20) [cis]-pregnadiene-3 ones by esterification of the 21-hydroxy group, e. g., by reaction with the appropriate acid anhydride, in the presence of a basic catalyst such as pyridine or sodium acetate. Exof Y 2-chloro-11 3-hydroxy-21-acyloxy-4,17(20)- [cis]-pregnadiene-3-one which can be prepared include those wherein the cyclopentylacetic, fl-cyclopentylpropionic, cyclohexylformic, cyclohexylacetic, B-cyclohexylpropionic, an aryl or alkaryl acid, e. g., benzoic, 2, 3 or 4-methylbenzoic, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and 3,5.-dimeth ylbenzoic, ethylbenzoic, 2,4,6-trimethylbenzoic, 2,4,6-tr1ethylbenzoic, a-

naphthoic, 3-methyl-a-naphthoic, an aralkyl acid, e. g., phenylacetic, phenylpropionic, diphenylacetic, tripheny1- acetic, etc.

EXAMPLE 8 2-ch Zora-1 113,1 7 oc-d ih ydroxy-Z] -acet0xy-4-pregn en e- 3,2 O-dione To a solution of 267 milligrams of 2-chloro-11fl-hydroxy-Zl-acetoxy-4,17(20)-[cis]-pregnadiene-3-one solved in thirteen added 0.127 milliliter of pyridine followed by a solution of 245 milligrams of N-methylmorpholine oxide peroxide and most of the tertiary butyl alcohol distilled from the chloro -l 1 8,21-dihydroxy-4,17(20)-[cis]-pregnadiene 3- one is converted to 2-chlorohydrocortisone.

EXAMPLE 9 2-ch lore-115,1 701,21-trihydroxy-l-pregnene-3,20 a'i0ne A solution of 438 milligrams of 2-chlorohydrocortisone acetate in four milliliters centrated by distillation at room temperature and reduced pressure and then chilled in a refrigerator for sixteen hours. The precipitated 2-chlorohydrocortisone is filtered and dried.

pared by substituting the corresponding Z-halo-llfill-dihydroxy-4,l7(20)-[cis]-pregnadiene-3-one fOL'lhB 21- acetate employed in the oxidative hydroxylation reaction. It is to be understood that the'invention is not to be limited to the exact detailsof operation or exact compounds shown and described, as obvious modifications and equivalents will be apparent to one skilled in the art, and the invention is therefore to be limited only by the scope of the appended claims. H i 1 We claim: a v

I 1. A compound selected from the group consisting of 2 chloro-ll5,2l-dihydroxy-4,l7(20)-[cis] -pregnadiene 3- one and 21-acy1 esters thereof represented by'the following formula; i v v HsC wherein R is selected from the group consisting of hydro-- gen and the acyl radical of a hydrocarbon carboxylic acid containing from one to twelve carbon atoms, in-- clusive. a

2. 2-chloro-11B,2l-dihydroxy-4,l7(20)-[cis]-pregnadiene-3-one.

3. 2-chloro-1lfi-hydroxy-Zl-acyloxy 4,1?(20) [cisJ- pregnadiene-3-one wherein the acyl radical is that of a hydrocarbon carboxylic acid containing from one to eight carbon atoms, inclusive.

4. A compound according to claim 3 wherein the acyl radical is that of a lower-aliphatic acid.

5. Z-chloro-l lfi-hydroxy-Zl-acetoxy 4,17(20) pregnadiene-ll-one.

- tcisl- References Cited in the file of this patent UNITED STATES PATENTS 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF 2CHLORO-11B,21-DIHYDROXY-4,17(20)-(CIS)-PREGNADINE-3ONE AND 21-ACYL ESTERS THEREOF REPRESENTED BY THE FOLLOWING FORMULA 